Effect of non-tuberculous mycobacteria on the protective efficacy of BCG vaccine via modulation of mucosal immunity

Tuberculosis (TB) continues to increase worldwide despite vigorous attempts to control it. Bacillus Calmette-Guerin (BCG) is the only licensed vaccine currently available for protection against TB, however, its efficacy is highly variable between countries. It has been hypothesized that BCG’s variable protection is due, amongst others, to immunological interference by environmental, non-tuberculous mycobacteria (NTM). However, a definitive mechanism has not been identified so far. Considering the foregoing, we developed a murine model closely resembling the natural history of human exposure to different mycobacterial species, including: 1) BCG vaccination at an early age; 2) exposure to viable NTMs (Mycobacterium avium subsp. avium) via the oral route and 3) maintaining continuous NTM exposure even after TB infection, as occurs in endemic places. Surprisingly, we found that a low dose of NTM via the oral route enhanced BCG-mediated protection 30 days post infection, as determined by decreased TB burden in lungs and spleens of infected mice. We hypothesized that upon oral intake, NTMs would interact with intestinal Peyer’s Patches (PPs) and activate mucosal immune responses. Therefore, we evaluated immune cell populations present in PPs and lungs using flow cytometry. Fifteen days after initiating NTM feeding, higher influx of B220hiMHC-IIhi B cells was observed in PPs of NTM exposed mice, regardless of BCG vaccination status. Similarly, NTM exposure augmented pulmonary CD62LintMHC-IIhiCD19hiB and CD4+ T cells. These results suggest that NTM exposure via the oral route elicit humoral mucosal immunity against TB, and this will be further dissected to leverage mucosal NTMs as a strategy to boost BCG.